Capsule construction

ABSTRACT

A controlled release capsule comprises a male plug (2) formed of a water swellable hydrogel which is engaged within a neck portion (4) of a female body (6). The capsule contains a pharmaceutically active material. In contact with an aqueous medium, such as in the gastrointestinal tract, the hydrogel plug swells and becomes disengaged from the body, thereby releasing the active material. In order to facilitate insertion of the male plug into the neck of the body, the body has a flared mouth portion (14) which is wider than the neck. The neck itself may be wider or narrower than the remainder of the body. A water-soluble cap (8) has detentes (18) which clip over the flared mouth portion so as to lock the cap thereto.

TECHNICAL FIELD

The present invention relates to a controlled release capsuleconstruction intended for containing a pharmaceutically active material,which comprises a male member engaged within a neck portion of a femalebody; the capsule including a water swellable material which swells soas to disengage the female body upon exposure of the capsule to anaqueous medium.

BACKGROUND

International Patent Specification WO 90/09168 discloses a device ofthis type which comprises a water swellable male plug engaged within afemale body. A pharmaceutically active material is contained within thedevice. When the capsule is exposed to water, the male hydrogel plugswells and eventually disengages itself from the female body, therebyallowing the pharmaceutically active material contained within thedevice to be released. It has been found that the time taken to releasethe pharmaceutical material is predictable and reproducible, so that thedevice may be used to release pharmaceutically active materials withinthe body of a patient after a predetermined time interval (e.g. 0.5 to12 hours). This may, for example, be useful in the treatment of medicalconditions where it is desirable to administer a pharmaceutically activematerial to the patient sometime through the night, while the patient isasleep, so as to provide a desired level of the drug in the patient inaccordance with his needs, for example during the night or when heawakes. It may also be useful to allow dosing of materials at apredetermined point as the capsule passes through the gastro-intestinaltract, for example in the colon.

Patent specification WO92/13521 (Alza Corporation) describesfluid-imbibing dispensing devices for delayed delivery of an activeagent, which include an expansion means which absorbs fluid from asurrounding environment. The dispensing device comprises a housinghaving first and second wall sections telescopically engaged with eachother, particularly a capsule having a hollow cap and a hollow body;either the cap or the body is in the form of a male section fittedinside the open end of the other female section. The expansion means iscontained within the device and expands as it absorbs fluid, forcingapart the two sections of the device. The expansion means may be aswellable polymer or an osmotic formulation which swells as it absorbsfluid. In order to allow fluid to come into contact with the expansionmeans contained within the device, one of the wall sections adjacent tothe expansion means is fluid-permeable. After the sections aredisengaged, fluid enters the device and comes into contact with theactive agent contained within the device, thereby dispensing the activeagent into the fluid.

Conventional hard gelatin capsules are produced and filled in largenumbers using high speed automatic machinery. Such capsules comprise abody and a cap. Normally the cap is pre-fitted to the capsule bodyduring manufacture of the capsule. During filling, the filling machineremoves the cap, fills the capsule with pharmaceutical material, andthen replaces the cap in a manner such that the cap is locked onto thecapsule body. Patent Specification U.S. Pat. No. 3,399,803 discloses aself-locking medicament capsule wherein the body has a groove near itsopen end, and the cap has a corresponding ridge which snags into thegroove so as to lock the cap and body together. U.S. Pat. No. 4,442,941discloses a bayonet-type arrangement whereby a raised portion on the capis engaged into a groove on the body.

European Patent Specification 246804 also discloses a capsule bodyhaving a groove near its mouth for the purposes of preventing thecapsule distorting from its cylindrical form, which may cause difficultyin fitting the cap onto the capsule body.

A preferred embodiment of the controlled release capsule with which thepresent invention is concerned (and as disclosed in WO 90/09168)requires that a male hydrogel plug be a close fit within the neck of thefemale capsule body so that the plug is firmly retained and does notdetach prematurely.

The hydrogel plug prior to hydration is a fairly rigid material. Forthese reasons, it may be difficult to insert the tightly fittinghydrogel plug into the mouth of a conventional cylindrical capsule bodyusing high speed machinery. If the body is slightly oval, or the plugand body are not perfectly aligned, there is a danger that the plug willcrush or crack the mouth of the capsule body during insertion.

It is an object of the present invention to mitigate this problem.

SUMMARY OF THE INVENTION

The present invention provides a controlled release capsule whichcomprises a male member engaged within a neck portion of a female body;the capsule including a water swellable material which swells so as todisengage the female body upon exposure of the capsule to an aqueousmedium; the body comprising a flared mouth portion adjacent the neckportion, the mouth portion having an entrance which is wider than theneck portion and wider than the male member so as to facilitateinsertion of the male member into the neck portion; and the neck portionof the female body being narrower than the remainder of the body.

The flared mouth portion provides a ramped lead-in, so that the malemember may be inserted readily into the neck of the female body.Usually, the mouth portion is flared at an angle of 10° to 60°(preferably 15°-45°) to the line of the capsule. In order to facilitateinitial positioning of the male member prior to insertion into the body,the flared mouth may be belled out into a substantially cylindricalentrance portion adjacent the entrance to the body, which is normally ofsubstantially the same diameter as the female body.

Usually, the capsule body and the neck portion thereof are ofsubstantially cylindrical configuration according to conventionalpractice.

In addition to the flared mouth portion, in one embodiment the neckportion is narrower than the remainder of the body. This enables theflared mouth portion to still be within the overall diameter of thecapsule body. A flared mouth portion extending beyond the line of thecapsule body may pose problems in handling using high speed fillingmachinery. Recessing the neck portion in this way may also contribute tothe overall strength of the neck portion and minimises splitting.Preferably, the neck portion has a diameter which is 80% to 99% (usually90 to 98%) of the diameter of the female body. Furthermore, it ispreferred that the maximum diameter of the entrance of the flared mouthportion be substantially the same as the diameter of the female bodyitself.

Preferably, the capsule body is prepared by conventional capsule formingtechniques, which involve dipping a mould pin in a solution of thematerial (such as gelatin) from which the capsule is to be formed.Spraying could be used instead of dipping. The gelatin is then dried andstripped from the pin. The capsule body may then be trimmed asnecessary. The presence of a narrow neck portion which is narrower thanthe body makes it somewhat more difficult to strip the capsule body fromthe mould pin, compared to conventional cylindrical capsules.Alternatively, the capsule might be made by other known capsulemanufacturing techniques, such as injection moulding of thermoplasticmaterials.

The walls of the female body may be formed from a wide variety ofmaterials. They may be of homogenous constructions or they may belaminated. Examples of materials suitable for use in the construction ofthe body include polyethylene, polypropylene, poly(methylmethacrylate),polyvinyl chloride, polystyrene, polyurethanes, polytetrafluoroethylene,nylons, polyformaldehydes, polyesters, cellulose acetate and nitrocellulose.

However, a preferred construction uses an impermeable coating to coverthe exterior of a body which has been formed from a water solublematerial. The coating may conveniently be formed by dipping the body ina solution of a material which forms a layer which is impermeable towater. Alternatively, the body might be spray-coated. A preferred classof capsule bodies are conventional hard gelatin or starch capsule bodiescoated with a solution of polyvinyl chloride or a polyvinyl acetatecopolymer or an ethyl cellulose solution.

In a preferred embodiment, the male member is a plug; usually ofcylindrical configuration. The plug is formed of the water swellablematerial, which is preferably a hydrogel. As it absorbs water, thehydrogel plug swells and becomes disengaged from the female body. Thehydrogel is preferably a water swellable material as disclosed in patentspecification WO90/09168.

Usually the neck portion is substantially cylindrical, so as to form atight fit with the cylindrical male plug.

In another embodiment, the male member is a hollow member closed at oneend, whose opposite open end engages within the neck of the female body.A water swellable material is provided within the capsule which servesto disengage the female body after a predetermined time, by forcing themale member and the female body apart as the material swells in thepresence of water. The swellable material inside the capsule may be anosmagent or an osmopolyer. Such an arrangement is disclosed inWO92/13521. In order to allow water to enter the capsule and to contactthe water-swellable material a portion of the wall of the capsuleadjacent thereto is preferably semipermeable; that is to say it ispermeable to the passage of water into the device but impermeable torelease of other substances from within the capsule.

Another aspect of the invention relates to a process of filling thecapsule, which comprises storing caps and bodies separately, filling abody with active material, inserting the male member into the neck ofthe body, and fitting a cap over the open end of the body.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a first embodiment of a controlledrelease capsule structured in accord with the principles of the presentinvention;

FIG. 2 is a top view of the capsule of FIG. 1, having the cap portionremoved;

FIG. 3 is a partial, elevational view of a second embodiment of capsulestructured in accord with the principles of the present invention; and

FIG. 4 is a partial, elevational view of a fourth embodiment of capsulestructured in accord with the principles of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Embodiments of the present invention will now be described by way ofexample only in conjunction with the drawings wherein:

FIG. 1 is a cross-sectional elevation of a first embodiment;

FIG. 2 is a view from above with the cap removed; and

FIG. 3 is a partial elevational cross-section of a second embodiment.

The capsule shown in FIGS. 1 and 2 comprises a male member in the formof a plug 2 formed of a hydrogel material, inserted in neck 4 of femalebody 6. The capsule is closed with a cap 8.

The body 6 comprises a cylindrical main portion 10 and closed end 12.The main body narrows to the neck portion 4 at a shoulder region 5. Theneck portion is substantially cylindrical so as to receive the male plug2 with a close tolerance. The neck portion then flares out to a flaredmouth portion 14 which has an entrance 15 of a diameter substantiallythe same as the diameter of the main body portion 10.

The cylindrical neck portion is advantageously provided with a ventchannel 16 shown in dotted lines which extends from the flared mouthportion part way down the neck portion and allows the release ofpneumatic pressure from within the capsule body during insertion of theplug. However, the vent channel extends only part way down the neckportion, so that when the plug is fully inserted into the neck, it sealswith the lower region of the neck where the vent channel is absent. Asshown in FIG. 2, a vent channel 16 may be provided on either side of theneck as required.

The male plug 2 is formed of a hydrogel material (such as disclosed inWO 90/09168) and is usually inserted so that the upper end of the plugis level with or below the upper end of the capsule body.

The capsule is then sealed with the cap 8 which is provided withdetentes 18 which clip under the rim of the flared mouth portion therebylocking the cap in place.

The cap has a cylindrical skirt portion 9 which extends down to the openend of the cap. The lower end of the skirt portion extends downwardlypast the shoulder 5 of the body and encloses an upper part of the bodywith only a small clearance. This helps to stabilise the cap and preventit tilting from side-to-side. It also allows the cap to be sealed to thebody by means of an annular band passing over the junction therebetween.

The cap is formed of a water soluble material, such as gelatin. Thecapsule body is formed of a water insoluble material, which may be awater insoluble plastics material or may be gelatin coated with awater-impermeable coating.

The capsule body is formed in conventional manner by dipping a mould pininto a gelatin solution and allowing to dry. The gelatin is then coatedwith a water-impermeable coating (e.g. by dip-coating) after the capsulebody has been stripped from the mould pin and trimmed to size.Alternatively, the water-impermeable coating may be applied by spraycoating or vapour deposition. The cap 8 is then temporarily fitted overthe capsule body such that the detentes 18 do not lock over the rim ofthe flared mouth portion. The pre-assembled empty capsule is then storedfor later filling. During filling, the cap is removed from the capsulebody, and a pharmaceutically active material is filled into the capsulebody. The hydrogel plug is then fitted into the neck of the body.Finally, the cap is replaced over the end of the capsule body and pusheddown so that the detentes 18 clip over the rim of the flared mouthportion, thereby locking the cap in place.

However, the preassembly step is not essential. The caps and bodies maybe stored separately and fed separately to the filling machine,particularly if precautions are adopted to prevent the caps nestingtogether and the bodies nesting during storage and feeding in thefilling machine. The narrow neck construction shown in FIG. 1 helpsminimise nesting of the bodies. A flattened cap shape, increased widthof the dome of the cap, or increased cap wall thickness helps minimisenesting of caps.

When the capsule is administered to a patient, the aqueous environmentin the gastrointestinal tract quickly dissolves the water soluble cap.Water is then absorbed into the hydrogel plug 2, which swells and isexpelled from the body after a predetermined time interval (for example2 to 10 hours). This allows the contents of the capsule to be releasedinto the patient's gastro-intestinal tract.

FIG. 3 shows a second embodiment which is similar to the firstembodiment, except as regards the shape of the flared mouth portion andthe extent of the vent channel. The cap is omitted for simplicity.

Thus, the vent channel 17 extends through the full length of thecylindrical neck portion, so that even when the plug is fully inserted,a total seal is not achieved. Such a construction may be easier todemould than the shorter channel shown in the previous embodiment.

The flared mouth portion 14 is belled outwardly, such that the entranceregion 15A to the body portion is substantially cylindrical and of adiameter substantially the same as that of the main portion 10. Thisfacilitates location of the plug in the mouth of the body prior to beingfully inserted.

Whether the plug is inserted proud of the neck portion, flush with theupper end neck portion, or is recessed below the upper end of the neckportion can affect the time taken to expell the plug. This time will bechosen according to the desired release time of the capsule contents.

We claim:
 1. A controlled release capsule which comprises a male member(2) engaged within a neck portion (4) of a water-impermeable female body(6); the capsule including a water swellable material which swells so asto disengage the female body upon exposure of the capsule to an aqueousmedium;the female body comprising a flared mouth portion (14) adjacentthe neck portion, the mouth portion having an entrance (15) which iswider than the neck portion and wider than the male member so as tofacilitate insertion of the male member into the neck portion; and theneck portion of the female body being narrower than the remainder of thebody; and the male member comprising a plug, and the plug being formedof said water swellable material.
 2. A capsule according to claim 1wherein the neck portion of the female body is substantiallycylindrical.
 3. A capsule according to claim 1 wherein the mouth portion(14) is flared at an angle of 10° to 60° to the longitudinal directionof the neck portion.
 4. A capsule according to claim 1 wherein theflared mouth is belled out into a substantially cylindrical entranceportion (15).
 5. A capsule according to claim 4 wherein thesubstantially cylindrical entrance portion is of substantially the samediameter as the female body.
 6. A capsule according to any precedingclaim wherein the female body and the neck portion are substantiallycylindrical and the neck portion has a diameter which is 80 to 99% ofthe diameter of the female body.
 7. A capsule according to claim 1 whichfurther comprises a cap (8) of a water soluable material, the cap havinginwardly extending protrusions (18) which clip over the flared mouthportion (14) of the female body to lock the cap in place on the femalebody.
 8. A capsule according to claim 7 wherein the neck portion of thefemale body is substantially cylindrical; and wherein the cap has anopen end and a skirt portion (9) adjacent thereto, the skirt portionenclosing a party of said remainder of the female body.